3alpha-amino-allopregnanes



United States Patent 3,102,895 3a-AIVHND-ALLOPREGNANES Jean Louis Paul Mainil, fioitsfort, Belgium, assiguor to SocieteAnonyme @letta, Luxembourg, Luxembourg No Drawing. Original application Sept. 26, 1958, Ser.

No. 763,431. Divided and this application June 12,

1962, Ser. No. 201,790

Claims priority, application Belgium dept. 27, 1957 6 Claims. (Ci. 260-3975) divisional based on my earlier application, Serial No.

763,431, filed September 26, 1958.

Investigations have shown that crystallizable alkaloids and principles, combined with the latex of this plant, can be isolated in an advantageous and economic yield from this species of -the genus Funtumia and from any part of the plant These alkaloids and bases are useful in veterinary therapy and as an intermediary product (raw product) for synthesis of other steroids. More particularly, the alkaloids are useful in controlling respiratory action and the nervous systems of animals. They are two in numher, and are hereinafter called alkaloids A and C, respectively.

The physiological properties of alkaloids A and C have been the subject of experiments and more detailed particul-ars will hereinafter be given.

For the isolation of these products, use is made of one of the methods generally employed for the isolation of alkaloids from plants, account being taken of the fact that each fraction is combined with the latex and/or the chlorophyll of the plant.

The plants or parts thereof, such as the leaves, trunk bark or roots, depending on the season at which the crop is taken, are crushed and then washed in petroleum ether. The cells are burst by a current of steam or by other chemical or physical means. The plants are then made alkaline with a solution either of 20% ammonia or of 10% or sodium carbonate, or with milk of lime or of magnesia, or they are moistened with water.

After contact for several hours with the alkaline medium, the plant is extracted in a Soxhlet apparatus, a mixer, a percolator or a rotative extractor, with petroleum ether, ether, benzene, chloroform, ethyl acetate or other solvents polar or non-polar chlorinated or non-chlorinated, alone or in admixture.

, Action on the central After complete extraction of the plant with one of these solvents or a mixture thereof, the extracts are stirred with a solution of acetic, hydrochloric, oxalic or other acid sufficiently strong to displace the principles com bined with the rubber and with the chlorophyll. It is generally desirable to use concentrations of at least 25%,

or a mixture of solvents immiscible with water, such as ether or chloroform, or miscible with water, such as ethyl or methyl alcohol. and is dried, the residue consisting of the alkaloids 0r bases mixed with other substances and resins heretofore regarded as impurities.

On distillation, a residue is obtained- EJhZQSdS These substances A and C are taken up individually in methanol and, if desired, recrystallized several times.

The substance having a melting point of 260 C. can also be obtained by distilling or otherwise treating the extraction solvents after elimination of the basic principles and of the chlorophyll and by recrystallizing this substance from, for example, methanol or ethyl acetate.

Experience shows that the product obtained is a sapogenin which is positive to Liebermanns reaction. Its infra-red spectrum shows an OH band at about 3 m and a CO band at about 6 m This substance contains no nitrogen.

The crude residual mixture of alkaloids and bases can alsobe obtained by extraction with acid water or neutral or acid alcohol by concentrating and extracting the residue by means of a solvent immiscible in the alkaline phase.

The residual mixture can be directly treated by successive recrystallizations until pure principles are obtained.

The chemical characteristics of bases A and C are as follows.

Alkaloid (principle) A-- Empirical formula: C H ON Developed formula: 3-a-amino-allopregnane-20-0l Infrared spectrum: OH, NH bands at about 3 no C=O bands. Its chlorhy-dr-ate has at 2080 cma band HN Melting point: 182 C. [or] =i0 in methanol.

Gives a hydrochloride of M.P. 290 C. Alk-aloid (principle) C-- Empirical formula: C I-I ON Developed formula: 3nut-amino-all0pregnane-20-oue. Melting point: 123 C. i It gives a hydrochloride of MP. 280 C. having a rotatory power of in methanol and the infra-red spectrum of which exhibits NH bands in the region of 3,14, a NH band at 4.9 a C=O band at about 5.9;; and

another band at about 6.2a,

C=C. vibration.

Toxicity DL Alkaloid A, 23 rug/kg.

Alkaloid o, 30 mgu/kg.

nervous system.

5 times more anaesthetic than cocaine on the cornea of the rabbit. Temperature reducer and 4 antipyretic. antipyretic. Oardrotourc On the isolated On the isolated auricle. 0n the auricle. On the rabbit's heart in rabbits heart in situ. sltu. Respiratory analeptic. On thc normal rabbit On the normal rabbit and on the morand on the me- I pli'mizcd rabbit. phinized rabbit. Cardiovascular .Vasodilatation hypo- Vasodilatstion hypotension. tension. 1&1dney Diuretic No action. Anabolic Slightly per os nil by Hormonal and metainjection. N0 oestrogenic action.

No ocstrogenic action.

bolie action. No androgenic action. No iolliculino-stimu- N o folliculino-stimulant action. lant action.

Suprarenal. Weight unchanged Weight unchanged after 40 days as after 40 days as compared with compared with controls. Ascorbic controls. Ascorbic acid and cholesterol acid and cholesterol content unchanged content unchanged as compared with as compared with controls. controls.

Liver Slight increase in dry Prevents glycogen weight. Prevents depletion of the glycogen depletion liver (like cortisone).

of the liver (like cortisone) Tranquilizmg Action 25 rug/kg. per day reduces the motility of rats by changing the number of movements re corded in 6 hours fi'OIIIl 16,500 to 2,500.

area-ass Inject-able solutions containing mg./cc. of the hydrochloride of alkaloid A or C can be prepared by dissolving distilled water alone.

It is also possible to prepare tablets for therapeutic use by using, for example, the following recipe:

Hydrochloride of alkaloid A or C mg. or mg. Lactose 71 mg. or 56 mg.

-Rice starch 8 0 mg. or 80 mg.

Magnesium stearate 2 mg. or 2 mg. Talc 37 mg. or 37 mg.

For example, the alkaloid and the lactose are granu lated. After drying, the other ingredients are added to enable ready dissolution in the stomach and lubricants to enable ready compression of the tablets.

Principles A and C maybe converted into mineral salts, such as sulphates, hydro-chlorides, nitrates or hydrobromides, or into organic salts,'such as tartrates, citrates, gluconates, camphorates, camphosulfonates and acetates.

For the production of hydrochlorides of bases A and C, the purified base in suspension in very hot water may be employed as starting material. The pH value is adjusted to 4 with a mixture of methanol and hydrochloric acid and the white hydrochloride is allowed to cool. They are very sparingly soluble in the cold.

Thealkaloids A and C, hereinafter called Funtumidine and Funtumine, respectively, may be used as starting materials for the production of other steroids, particularly for obtaining dihydro-progesterone in an advantageous yield (allopregnane-3-20-dione).

It is particularly advantageous to obtain these substances by preparing the chloramine by action of hypoi c'hlorous acid in ethereal'solution. This chloramine is dechlorinated by means of sodium ethylate and the ketamine obtained is hydrolyzed in sulphuric acid solution to give allopregnane-3-20-dione in a good yield.

EXAMPLE C., with agitation. The entire operation is carred out in the presence of anhydrous sodium sulphate so as to avoid the presence of water.

The ethereal hypochlorous acid solution is prepared b the method of Wohl and Goldschmidt, Ber. 46; 2731 1913). After agitation for one hour, the ethereal solution is filtered to separate the sodium sulphate, and is evaporated to dryness in vacuo. The crystalline residue is boiled under reflux for 40 minutes with a solution of sodium ethylate in 50 ml. of absolute ethanol. The solution is thereafterpoured into 300 ml. of water slightly acidified with sulphuric acid. The mixture is allowed to stand for 24 hours and the precipitate formed is suction filtered and dissolved in chloroform. The chloroformic solution is washed with water, dried and evaporated to dryness in vacuo. A residue weighing 1800 mg. is obtained.

After recrystallization from hexane and alcohol, al-

1 lopregnane-3-20-dio ne, M.P. ZOO-202 C. and (00 +128 (CHCl is obtained.

By the same method, alkaloid A or its 20-position epimer can be converted into the two sterolic alcohols 20- hydroxy-allopregnane-3-one.

Alkaloid A is advantageously oxidized to vgive alkaloid The calculated quantity of hypochlorous acid in ethe- V real solution, cooled to 20 C. (the quantity is calculate-d mol. per mol.) is added dropwise to 1 gram of alkaloid C in solution in ethereal solution cooled to- 10 C in ketonic form by the use of chromic acid in acetic acid solution or by any other method.

Alkaloid A Alkalold O Z 0 CrOa The invention also concerns the production of derivatives of alkaloid C. (Funtumine) preserving the amino function in the 3-p-osition, :as follows: v

(1) Reduction of the ketone function of alkaloid C into an alcohol function (Funtumidine) 3-oi-amin0-20-B-hydroxy-allopregnan eFuntumidine.-

alcohol is driven off by distillation in vacuo and the residue is taken up in water and extracted with methylene chloride. The organic solution is dried over anhydrous sodium sulphate, filtered and distilled to dryness. The residue (200 mg.) is crystallized from ethyl acetate and gives the dihydrogenated derivative of Funtumine, which is identical with Funtu-midine, M.P. 178, (00 +10 (CHClg).

3 a amino-20-p-hydr0ocy-al!0pregnane20-epi-Funtumidine.-The epimer of Funtumidine is obtained by the reduction of Funtumine by means of potassium borohydride in solution in methyl alcohol.

200 mg. of Funtumine are dissolved in 10 cc. of methanol. To this solution are added 200 mg. of potassium borohydride. The mixture is constantly stirred for 5 hours at room temperature. The excess of borohydride is then entirely consumed. The solution is poured into cc. of water and the precipitate is extracted with an organic solvent such as ether or methylene chloride. The organic solution is dried and evaporated to dryness. The crystalline residue is recrystallized from ethyl acetate.

, mg. of ZO-epi-Funtumidine, M.P. 167 C., are obtained.

(2) Production of S-antino derivatives of androstane from Funtumine H one H \UVE) onzoosn lj-di l) Y Q What is claimed is:

l. A product selected from the group consisting of 3-a-amino-allopregnane-ZO-ol and its therapeutically acceptable acid addition salt.

2. A product selected from the group consisting .of

5 6 3-a-aimino-allopregnane-20-one and its therapeutically 5. 3-a-amin0-a1l0pregnane20 one. acceptable acid addition salt. 6. The therapeutically acceptable acid addition salt of 3. 3-a amino-a.llopregnane-20-ol. 3-x-amino-allopregnane-20-0ne.

4. The therapeutically acceptable acid addition salt of 3-a-amin0-al1op regnane-ZO-ol. 5 No references cited. 

3. 3-A-AMINO-ALLOPREGNANE-20-OL.
 5. 3-A-AMINO-ALLOPREGNANE-20-ONE. 